Over the past decade many successes in identifying mutations responsible for human illness have been for relatively uncommon diseases which are inherited in simple mendelian patterns. More recent years have seen attention turn to understandgenetic alterations associated with common diseases such as cancer, diabetes and a variety of neurodegenerative disorders. Several lines of evidence suggest that such mutations might be present at high frequencies, have low penetrance and involve distinct genes in different individuals with similar phenotypes. Further, it is likely, that interactions between multiple genetic and environmental factors are required before disease develops. As a practical matter, it is often easiest to identify these types of mutations in genetically homogeneous populations. Once such group are Ashkenazi Jews of eastern and middle European origin. Although there is no evidence that they have an overall greater burden of genetic illness than other groups, common mutations most likely due to founder effect and genetic drift have been detected at a comparatively high frequency. A recent study examining the penetrance of common founder mutations in BRCA1 and BRCA2, two genes associated with inherited forms of breast cancer, resulted in the collection of DNA samples and family histories of cancer from a sample of approximately 5000 Ashkenazi Jews from the Baltimore-Washington area. These valuable resources provide powerful tools for the characterization of common DNA sequence variations potentially associated with the development of cancer. We recently determined the risk of colon and breast cancer associated with a particular mutation in the APC gene (I1307K). Mutations in other genes with common, potentially disease-associated alleles will be investigated for increased cancer risk in the above-mentioned cohort of Ashkenazim. This will include genes related to folate and carcinogen metabolism. A second series of experiments aimed at identifying genes which modify the risk of cancer are currently being designed. In these studies individuals known to carry mutation in their BRCA1, BRCA2 or APC genes will be collected. The DNA from persons with a mutation and affected with cancer will be compared to the DNA from older individuals who carry mutations and have remained cancer free. Regions of the genome that differ between these individuals should correlate to the location of genes that act to increase or decrease cancer risk. - breast cancer, BRCA1/2, carcinogen, ovarian cancer, genetics, Womens's Health Research - Human Subjects